Inactivation of tumor-suppression genes (TSGs) in cancer is often a two-step process, involving a mutation of the target gene and additional loss of the wild-type allele. Mapping of chromosomal deletions and losses of heterozygosity in cancer cells has been widely applied to guide the identification of TSGs. However, this approach alone is slow, labor-intensive and complicated by genomic instability, often leading to numerous candidate regions to study. In an alternative approach, the nonsense-mediated RNA decay (NMD) mechanism, which normally targets transcripts with nonsense mutations for rapid degradation, can be blocked to cause differential stabilization of genes that harbor truncating mutations. By using microarrays to measure transcript levels following NMD inhibition, this approach has recently been proposed for genome-wide identification of mutated genes in cell lines.